Ni-Mediated Inter- and Intramolecular Conjugate Addition of Aryl

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Ti/Ni-Mediated Inter- and Intramolecular Conjugate Addition of Aryl and Alkenyl Halides and Triflates Irene R. Márquez,† Delia Miguel,† Alba Millán,† M. Luisa Marcos,‡ Luis Á lvarez de Cienfuegos,† Araceli G. Campaña,*,† and Juan M. Cuerva*,† †

Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain Departamento de Química, Universidad Autónoma de Madrid (UAM), Cantoblanco, E-28049 Madrid, Spain

‡

S Supporting Information *

ABSTRACT: In this work, we show that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to α,βunsaturated carbonyls at room temperature, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds inter- and intramolecularly with good functional group compatibility, which is key for the development of free protecting group methodologies. Carbo- and heterocycles of five- and six-membered rings are obtained in good yields. Moreover, some insights about the mechanism involved have been obtained from cyclic voltammetry, UV−vis, and HRTEM measurements.

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INTRODUCTION The radical conjugate addition constitutes an important transformation in organic synthesis. It is known that nucleophilic radicals generated from organic halides with nBu3SnH can react with electron-deficient alkenes.1 However, phenyl and vinyl radicals are highly reactive,2 and side reactions are of greater concern, giving addition products in only modest yields. Moreover, initiation reaction typically requires a radical initiator combined with high temperatures or irradiation. It is worth noting that easily prepared triflates are not yet suitable starting materials in these radical transformations. An interesting alternative is the use of metal-based single-electrontransfer (SET) reagents such as SmI2. Nevertheless, the use of SmI2 is mainly restricted to conjugative addition reaction of alkyl halides to α,β-unsaturated esters and amides.3,4 Although the use of aryl halides in SmI2-mediated conjugative cyclizations has also been demonstrated, it is restricted to the formation of oxindoles.5 Therefore, a method for the direct conjugate addition of aryl and alkenyl iodides and bromides to a variety of conjugated carbonyl compounds with high functional-group compatibility and wide substrate scope would be valuable in organic synthesis. The reductive Heck reaction represents an alternative to this radical conjugate addition because identical final products are obtained in both reactions. Even though the Mizoroki−Heck reaction has been extensively studied, the reductive conjugative addition has received much less attention (Scheme 1, path b).6,7 Building upon the pioneering works of the Cacchi group,8,9 the Pd-catalyzed intermolecular conjugate addition of aryl and vinyl halides has been developed. Nevertheless, most of the protocols were restricted to the use of enones or enales8−10 and β-nitrostyrenes.11 The use of α,β-unsaturated esters as electrophiles is still very limited and to the best of our © 2014 American Chemical Society

Scheme 1. Different Approaches to Conjugate Addition Reactions

knowledge is restricted to only one example of intermolecular addition, yielding mixtures with nonreductive Heck coupling product.12 Remarkably, the corresponding intramolecular Pdcatalyzed conjugated addition is limited to the use of enones as activated alkenes13−15 for the synthesis of five-membered carbocycles at high temperatures15 while the intramolecular Pdcatalyzed conjugated addition to α,β-unsaturated esters of Received: November 27, 2013 Published: January 29, 2014 1529

dx.doi.org/10.1021/jo402626u | J. Org. Chem. 2014, 79, 1529−1541

The Journal of Organic Chemistry

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of a Ni catalyst with a Lewis acid such as Cp2TiCl. The first general intramolecular protocol is described giving rise to carbo- and heterocycles of five- and six-membered rings. Noteworthy, the coupling of aryl chlorides and triflates under mild conditions is also demonstrated. Finally, a general mechanism for the reductive conjugate addition is presented.

amides has not been reported. On the other hand, intermolecular conjugative addition of vinyl triflates has also been shown,12 but it is strongly dependent on the nature of the β-substituted-α,β-unsaturated carbonyl compound, and mixtures with Heck type products are obtained. It has also been shown by Gosmini that cobalt catalysts can efficiently promote the direct conjugate addition of aryl halides and triflates onto activated olefins.16,17 Trapping of the metal enolate by an aldehyde has also been used in domino reactions.18,19 It is noteworthy that the intramolecular protocol has not been reported in any case. Nickel-mediated reductive Heck reactions have also been described. Intermolecular conjugative additions of aryl and alkenyl halides to activated carbonyls have been reported involving final protonation of the resulting nickel enolate.20−25 These protocols are usually restricted to the intermolecular coupling of aryl bromides with acrylates at high temperatures. Trapping of the nickel enolate by an aldehyde or by silicon reagents has been described by Montgomery26,27 and Weix,28,29 respectively. Interestingly, in this latter case, Weix has also recently demonstrated that the addition proceeds via an allylnickel intermediate,29 describing the first catalytic application of the use of allylnickel(II) reagents previously reported by Mackenzie.30,31 Nevertheless, this approach based on allylnickel intermediates is still limited to the intermolecular coupling of enones or enals as activated alkenes (Scheme1, path c). Nicatalyzed intramolecular conjugative additions are restricted to the reported coupling of a vinyl halide to an enone,32 an enal,33or an acrylate34 in three isolated examples employed in natural product synthesis. Furthermore significant excess of Ni(cod)2 catalyst (1.5−6 equiv) was necessary in all cases. To the best of our knowledge, Ni-catalyzed intramolecular reductive conjugative addition of aryl halides has not been described. Direct conjugate addition of aryl and vinyl organometallic reagents to α,β-unsaturated carbonyls constitutes other important transformation in organic synthesis, yielding similar final products. In this context, the use of copper salts has been widely described for conjugate additions from Grignard or lithium derivatives (Scheme 1, path d).35 Nevertheless, limited functional-group compatibility has motivated the use of other transition-metal catalysts, such as rhodium36 or palladium,37 combined with more convenient addition of less reactive carbon nucleophiles, such as organozinc,38,39 organozirconium,40 or organoborane41 compounds. These strategies represented an enormous progress in this field, expanding the scope of the reaction and improving FG tolerance. Nevertheless, the main weakness of those protocols is still the required preformed organometallic reagents, and functional group tolerance remains a challenge despite the advances reported so far. Although some metalated nucleophiles, especially boronic acid and derivatives, are easy to handle and prepare or commercially available, they are generally synthesized from the corresponding aryl halides, and consequently, extra synthetic steps might be necessary. Therefore, the direct use of aryl halides presents important benefits regarding experimental conditions and structural variety. Herein, we report a novel catalytic strategy which allows the direct inter- and intramolecular conjugate addition of aryl and alkenyl iodides and bromides to acrylates without requiring the previous formation of an organometallic nucleophile. Both good functional-group compatibility and wide substrate scope are displayed. The method is based on the unique combination

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RESULTS AND DISCUSSION Initially, we explored the feasibility of using the combination of a Pd or Ni catalyst with the unique features of Cp2TiCl,42−47 a SET reagent which can also act as a very efficient Lewis acid.48,49 Procedures based on palladium/titanium combination have proven to be capable of promote allylation,50 crotylation, prenylation,51 and propargylation52 of carbonyl compounds, as well as Michael-type addition53 using allylic carbonates as pronucleophiles. Oppolzer-type46 as well as Heck and reductive-type cyclizations54 of alkyl iodides have also been afforded by nickel/titanium-base procedures. These hybrid organometallic-radical protocols have shown good FG tolerance and broad substrate scopes since mild reaction conditions are employed.55,56 First, when model compound 1 was treated with the combination NiCl2/PPh3 and Cp2TiCl, generated in situ from the mixture Cp2TiCl2 and Mn dust, cyclic compound 2 was isolated in 72% (Scheme 2). However, when PdCl2 was used Scheme 2. Model Reactiona

a Reaction conditions: (i) 1 (1.0 mmol), Cp2TiCl2 (1.0 mmol), Mn (8.0 mmol), NiCl2 (0.2 mmol), PPh3 (0.4 mmol), TMSCl (4.0 mmol), THF, rt, 16 h, 72%.

instead of NiCl2, the expected Heck-type cyclization product was obtained. In this latter case, β-hydride elimination is fast and makes this strategy not suitable for the reductive conjugate addition. Therefore, the next studies focused on the Ti/Ni combination. Our initial experiments began with a study of the reagents directly involved in the reaction shown above. After a sequence of control experiments in which each reagent was removed, it was clear that Ni catalyst is indispensable (Table 1, entry 2). Moreover, as in all reductive couplings/additions, an electron source is required. In this case Mn was used as reducing agent Table 1. Control Experiments entry

Cp2TiCl2 (equiv)

NiCl2 (equiv)

PPh3 (equiv)

yielda (%)

1 2 3 4 5 6 7

1.0 0.7

0.2

0.4 0.4 0.4 4.0

72 0 ∼10 55 61 0b 0c

0.7 0.7 0.7

0.2 2.0 0.2 0.2 0.2

0.4 0.4

a

Yields correspond to isolated products after chromatographic purification. bMn dust was not added in this case. cMe3SiCl was not used in this case. 1530



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combination NiCl2/PPh3 (Table 3, entry 1 versus 6), which suggests that reduction of the preformed complex to the active Ni(0) species is slightly disfavored. Similar results were obtained when the reaction was performed with NiCl2, Ni(acac)2 or Ni(cod)2 as nickel source (Table 3, entries 1, 7, and 12). Good functional-group compatibility is a key element when it comes to the development of cyclization reactions. The features displayed by the protocol presented here make it ideal for an intramolecular protocol considering that it avoids preformed metalated nucleophiles. In this case, the compulsory polyfunctionalized compounds can be easily prepared.58 As shown in Table 4, the intramolecular reductive coupling of aryl iodides, bromides, chlorides, and even triflates to α,βunsaturated esters has been developed. Thus, when polyfunctionalized substrates 1, 3, 4, and 5 were submitted to optimized reaction conditions, cyclic compound 2 was obtained in good yield in all cases (Table 4, entries 1−4). Noteworthy, the intramolecular addition of aryl bromides, chlorides, and triflates to unsaturated carbonyls can be conducted at room temperature. To the best of our knowledge, this result (entry 4) constitutes the first example of an intramolecular reductive coupling of an aryl triflate. The intramolecular reductive coupling of aryl derivatives to activated alkenes, including α,β-unsaturated esters (entries 1− 9), ketones (entry 10), and amides (entries 11 and 12), allows the synthesis of different benzo-fused carbo- and heterocycles at room temperature having different electronic and steric profiles with moderate to good yields. Thus, the reaction takes place with electron-rich pronucleophiles as phenylsulfonamides (entries 7, 8, 11, and 12), as well as with benzylsulfonamides (entry 9) and benzylalkanes (entries 1−6 and 10). Moreover, the reaction proceeds well to give cycles of six (entries 1−6, 9, and 10) and five members (entries 7, 8, 11, and 12).59 Remarkably, this method allows an easy access to nitrogencontaining heterocycles structurally related with alkaloids such as dihydroindoles 10, tetrahydroisoquinolines 13, and dihydroindolones 17. Those benzo-fused nitrogen heterocyclic systems are of significant interest as potential pharmaceutical agents due to their action as enzyme inhibitors, receptor ligands, and hormone release promotors.60−62 Subsequently, intermolecular coupling of aryl halides with acrylates was tested under optimized conditions (Scheme 3). First, the coupling of iodobenzene with methyl acrylate was examined. Despite the potential for many undesired competing reactions such as the direct aryl halide reduction, acrylate reduction, or Heck coupling, the reaction was very clean, affording the desired reductive conjugate addition product 19 in 61% yield after 16 h at room temperature (Chart 1). A considerable excess of methyl acrylate was advisable as better yields were observed.63 A variety of activated alkenes was tested as reaction partners with iodobenzene, and although acrylonitrile, 5,6-dihydro-2H-pyran-2-one, and tert-butyl acrylate were coupled (Chart 1, compounds 20−22), the best result was obtained with methyl acrylate (Chart 1, 19). When unfunctionalized alkenes such as styrene or substituted methyl crotonate were used, coupling products were not observed.58 The results suggest that an appropriate coordination to the activated alkene is required. The scope of this process appears to be broad as the aryl iodide might also be functionalized with ethers, bromides, chlorides, tosylates, acetates, esters, silanes, or amides (Chart 2). Further FG tolerance is also demonstrated as derivatives

(Table 1, entry 6). Finally, Me3SiCl was also necessary (Table 1, entry 7). Lack of one of these individual components yielded starting iodide 1. Interestingly, we found that the presence of Cp2TiCl is very beneficial for the yield of the reaction (Table 1, entry 3). The required amount of the metal catalysts was optimized using the model reaction shown in Scheme 2. The results outlined in Table 2 show that the amount of both Cp2TiCl2 Table 2. Optimization of Metal Catalyst Loading entry

Cp2TiCl2 (equiv)

NiCl2 (equiv)

yielda (%)

1 2 3 4 5 6 7

1.0 0.7 0.5 0.2 0.2 0.7 0.7

0.2 0.2 0.2 0.2 0.1 0.1 0.2

72 76 63 54 50 64 57b

a Reactions were run in combination with 1 (1.0 equiv) PPh3 (0.4 equiv), Mn (8 equiv), Me3SiCl (4 equiv), THF, rt, 16 h. Yields correspond to isolated products after purification. bZn (8 equiv) was added in this case instead of Mn dust.

and NiCl2 can be considerably reduced to 0.2 and 0.1 equiv, respectively (Table 2, entry 5). However, the best yield was obtained by using Cp2TiCl2 in 0.7 and NiCl2 in 0.2 equiv amounts; therefore, we considered those as the optimal conditions to be used (Table 2, entry 2). The reaction run with Zn instead of Mn as co-reductor was also tested, although cyclic compound 2 was obtained in lower yield (Table 2, entry 7).57 A variety of Ni catalysts and ligands were also tested with model compound 1, and the results are summarized in Table 3. Table 3. Ligand and Ni Catalyst Effects entry

[Ni] cat. (equiv)

ligand (equiv)

yielda (%)

1 2 3 4 5 6 7 8 9 10 11 12

NiCl2 (0.2) NiCl2 (0.2) NiCl2 (0.2) NiCl2 (0.2) NiCl2 (0.2) NiCl2(PPh3)3 (0.2) Ni(acac)2 (0.2) NiCl2(glyme) (0.2) NiCl2(dppe) (0.2) NiCl2(PtBu3) (0.2) NiBr2 (0.2) Ni(cod)2 (0.2)

PPh3 (0.4) PCy3 (0.4) dppe (0.2) P(OPh)3 (0.4) bipy (0.2)

76 45 51 0 0 69 78 68 5 31 69 77

PPh3 (0.4)

PPh3 (0.4) PPh3 (0.4)

a Reactions were run in combination with 1 (1.0 equiv) Cp2TiCl2 (0.7 equiv), Mn (8 equiv), Me3SiCl (4 equiv), THF, rt, 16 h. Yields correspond to isolated products after purification.

Although the phosphorus ligand does not seem to be strictly required in this transformation (Table 1, entry 5), it might help in stabilizing low-valence nickel intermediates. Different phosphines could be used, including mono- and bidentade ligands. Nevertheless, the best yields were obtained with PPh3 (Table 3, entries 1, 7, 11, and 12). On the other hand, neither phosphites nor pyridine derivatives were suitable ligands for this transformation (Table 3, entries 4 and 5). Interestingly, preformed catalyst [NiCl2(PPh3)2] gave a lower yield than the 1531



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Table 4. Ti/Ni-Catalyzed Intramolecular Reductive Additiona

Scheme 3. General Intermolecular Reaction of Aryl Iodides and Activated Alkenesa

a

Reaction and conditions: (i) aryl iodide (1.0 equiv), acrylate (10 equiv), Cp2TiCl2 (0.7 equiv), NiCl2 (0.2 equiv), PPh3 (0.4 equiv), Mn (8 equiv), Me3SiCl (4.0 equiv), THF, rt, 16 h.

Chart 1. Products and Yields Obtained from Iodobenzene

Chart 2. Products and Yields Obtained from Aryl Iodides and Methyl Acrylatea

a

Yields correspond to isolated products after purification. bCompound 23 was isolated as a 10:1 mixture with methyl 3-(4-tosylphenyl)acrylate. cCompound 27 was isolated as a 10:1 mixture with methyl 3(4-chlorophenyl)acrylate. dCompound 28 was isolated as a 15:1 mixture with methyl 3-(4-carboxymethylphenyl)acrylate.

bearing a free OH are accepted (compounds 30 and 31), which represents a notable improvement compared to described methods base on nucleophilic aryl reagents. It is noteworthy that reactions with meta- and ortho-substituted aryl iodides yielded coupling products 29, 31 or 33, and 34, respectively.

a

Reaction and conditions: polyfunctionalized substrate (1.0 equiv), Cp2TiCl2 (0.7 equiv), NiCl2 (0.2 equiv), PPh3 (0.4 equiv), Mn (8 equiv), Me3SiCl (4.0 equiv), THF, rt, 16 h. bCompound 13 was isolated as a 5:1 mixture with reduced compound methyl 4-(N-benzyl4-methylphenylsulfonamido) butanoate. 1532



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However, lower yields are observed from ortho-substituted aryl halides showing that the steric hindrance at the organic halide plays a special role in the reaction pathway. The lower reactivity of bromobenzene compared to iodobenzene enabled the chemoselective coupling of 4bromo-1-iodobenzene (Chart 2, compound 25). Interestingly, unlike the intramolecular protocol, the intermolecular addition of aryl bromides to unsaturated carbonyls required heating the reaction mixture at 50 °C.64 Furthermore and despite of the harsher conditions employed, notable functional group compatibility is again displayed as ethers, tosylates, acetates, silanes, amides, or free alcohols are tolerated (Chart 3).

Scheme 5. Proposed Mechanism for Intermolecular Addition of Iodobenzene to Methyl Acrylate

Chart 3. Aryl Bromides Used and Yields Obtaineda

a

Yields correspond to isolated products after purification. bYield based on recovered starting material. ctert-Butyl acrylate was used in this case.

coordination of acrylate would generate Ni(II) complex I. This proposed structure is supported by the following experimental data. When model compound 1 (Scheme 2) was treated with stoichiometric amounts of a Ni(0) catalyst and Me3SiCl as Lewis acid in the absence of Mn dust, compound 2 was isolated in 70% yield, strongly supporting that only Ni(0) species are responsible for the initial step.66 Additionally, although external phosphorus ligands resulted in better yields (Table 2, entry 2), probably by stabilization of initial Ni(0) species, their use is not strictly required (Table 1, entry 5). Taking into account that the presence of a Lewis acid, such as Me3SiCl or Cp2TiCl, is mandatory and no other ligand is required, we suggest a specific coordination sphere for that Ni(II) complex I. This structure is also supported by the proposed intermediates for Ni-catalyzed reductive aldol addition of acrylates and aldehydes developed by Montgomery et al.27 Consequently, the steric hindrance of both interacting partners plays a crucial role, explaining the worse reactivity of ortho-substituted aryl halides (Chart 2, 34) and β-substituted activated alkenes.58 On the other hand, intramolecular coupling is favored and takes place at room temperature even when less active aryl bromides, chlorides, or triflates are used as electrophiles. Additional experiments were carried out to understand the role of phosphorus ligands. At first, we cannot rule out the interaction of phosphorus ligands with coordinative unsaturated Cp2TiCl. To clarify this point, the UV−vis spectra of a solution of Cp2TiCl in tetrahydrofuran (THF) were recorded. As increasing amounts of PPh3 were added to the solutions the UV−vis spectrum of Cp2TiCl did not change notably, suggesting that the increase in yield is exclusively owing to coordination with Ni complexes. Consequently, when the UV− vis spectra of solutions of Ni(acac)2 in THF were recorded in the presence of PPh3 they exhibited a marked alteration.67,68

The steric hindrance plays an important role not only at the organic halide but also at the activated alkene, as β-substituted alkenes do not afford any intermolecular addition product. An initial coordination of acrylate to Ni(0) seems necessary.58 In the intramolecular protocol, probably due to the proximity between the reactive centers induced by the substrate structure, subsequent oxidative addition and formation of the new C−C bond are easier, avoiding highly energetic intermediates. In addition to aryl halides, alkenyl halides have also shown good reactivity. As illustrated in Scheme 4, vinyl iodides and bromides have been reductively coupled to tert-butyl acrylate to form products 37 and 38.65 This novel Ti/Ni-mediated conjugate addition of aryl derivatives can be rationalized by the mechanism illustrated in Scheme 5. Oxidative addition of the aryl iodide to Ni(0) and Scheme 4. Intermolecular Coupling of Vinyl Halides and tert-Butyl Acrylatea

a Reaction and conditions: (i) vinyl halide (1.0 equiv), tertbutyl acrylate (10 equiv), Cp2TiCl2 (0.7 equiv), NiCl2 (0.2 equiv), PPh3 (0.4 equiv), Mn (8 equiv), Me3SiCl (4.0 equiv), THF, 50 °C, 16 h.

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The subsequent proposed step is a 1,2-insertion into the α,βunsaturated carbonyl, yielding nickel(II) enolate II. Instead of the usual β-hydride elimination process in the presence of Cp2TiCl, a transmetalation takes place to produce titanium(III) enolate III, recovering the initial Ni(II) catalyst. Typically, as commented above, when a Pd catalyst was used, fast β-hydride elimination ended the reaction yielding β-aryl α,β-unsaturated carbonyl products by a standard Pd(0)-catalyzed Heck reaction. A following trapping of such enolate III with trimethylsilane chloride would liberate titanocene(III) chloride to produce a silyl enol ether,69−71 which would lead to the final reduced product after an acidic workup.72 Ni(II) complexes have been extensively used in combination with Mn(0) as reductant, and therefore, initial activation of the NiCl2 by Mn dust could be assumed. Nevertheless, in our case, the lack of Ti(III) required a considerable excess of nickel catalyst being, therefore, indispensable for the regeneration of active Ni(0) species. To clarify this issue, electrochemical studies were carried out on a glassy carbon working electrode (Figure 1). First, the electrochemical properties of Ti(III) and

that the process is not a simple reversible one. Accordingly, in SWV the reduction process is composed by a large peak at Ep = −2.14 V followed by a smaller one at Ep = −2.63 V vs Fc+/Fc (Figure 2, solid line). In our hands, the potential for Cp2TiCl

Figure 2. Square wave voltammograms of 4 mM solutions of Ni(acac)2 (solid line) and Ni(acac)2 after being treated with Mn for 50 min (dashed line). Data recorded at 15 Hz in 0.15 M Bu4NPF6/THF.

solution oxidation was Ep = −0.89 V vs Fc+/Fc as measured from SWV, similar to the previously reported value74 and supporting that Cp2TiCl is probably incapable of reducing Ni(acac)2. The reduction of Mn(II) complexes occurs at more negative potentials compared to the Ni(II) complexes, and therefore the reduction of Ni(II) by Mn(0) is expected.75 Experimentally, after treatment of Ni(acac)2 with Mn(0) as stoichiometric reducing agent in THF for 50 min at room temperature, the CV was recorded (Figure 1c). Again, the cathodic scan showed two close reduction waves, which are partially reversible in CV and gave rise to peaks at −2.19 V and −2.61 V vs Fc+/Fc in SWV. However, in this case the second reduction wave becomes a clear peak in the presence of Mn (Figure 2, dashed line), supporting that Mn(0) had reduced some of the initial Ni(II). Lastly, in Figure 1d, CV for Ni(acac)2 in THF changed drastically upon addition of Cp2TiCl. The typical CV pattern of the Ni complex was no longer present, indicative of ligand exchange between the complexes.76 In addition, as shown above (Figure 1a), the cyclic voltammogram of Cp2TiCl complex is mainly characterized by irreversible waves. However, as can be seen in Figure 1d, in the presence of Ni(acac)2, a process corresponding to the full reversible Ti(III/IV) oxidation is exhibited at E1/2 = −0.85 V vs Fc+/Fc. Moreover, we observed the extinction of this Ti peak as long as a black precipitate was formed in the cell. This result indicates again a clear interaction between the two metal complexes. At this point, we wondered if this solid was obtained due to the voltage applied during the experiment. Therefore, we decided to further investigate the reaction between Cp2TiCl and Ni(acac)2. In a Schlenk flask, a light green THF solution of Cp2TiCl was treated with a THF solution of Ni(acac)2 under Ar atmosphere at room temperature. An immediate color change to dark green was observed and within the next 15 min a dark gray precipitate was produced. The mixture was allowed to stand unperturbed, and a black precipitated was obtained. To inspect in deeper detail the interaction between Ti(III) and Ni(II), high-resolution transmission electron microscopy (HRTEM) was used to characterize the solid precipitate obtained. Figure 3 shows a TEM image of the isolated solid. A closer examination of the images shows that particles in the 5−

Figure 1. Cyclic voltammograms of 4 mM solutions of: (a) Cp2TiCl; (b) Ni(acac)2; (c) solution of Ni(acac)2 after being treated with Mn for 50 min; (d) solution of Cp2TiCl, Ni(acac)2, and Mn; recorded at a sweep rate 0.1 V s−1 (a,b,d) or 0.05 V s−1 (c) in 0.15 M Bu4NPF6/ THF. Fc (ferrocene) or Fc* (decamethylferrocene) were added as internal standards at the end of a short series of experiments, and potential values are reported vs Fc+/Fc.

Ni(II) complexes were defined by cyclic and square-wave voltammetries (CV and SWV) conducted in THF solution containing 0.15 M Bu4NPF6 as the supporting electrolyte. Representative CVs for Cp2TiCl and Ni(acac)2 in THF solution73 are shown in parts a and b, respectively, of Figure 1. For Ni(acac)2, a very wide reduction peak with Epc = −2.44 V vs Fc+/Fc at 0.1 V s−1 (Fc = ferrocene) is shown in CV; upon scan reversal, an oxidation peak at Epa = −1.95 V vs Fc+/Fc appears (Figure 1b). The very large anodic to cathodic peak separation of ca. 500 mV (ΔE p for Fc and Fc*, decamethylferrocene, standards in the same solution was close to 100 mV) as well as the general CV shape indicate 1534



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Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: m = multiplet, quint = quintet, q = quartet, t = triplet, d = doublet, s = singlet, b = broad. Assignment of the 13C NMR multiplicities was accomplished by DEPT techniques. Cyclic and square wave voltammetry (CV and SWV, respectively) experiments were performed with a three electrode cell under N2 (>99.9995%) atmosphere at 25 °C. A Pt-mesh counterelectrode and an Ag-wire quasireference electrode were used. The working electrode was a glassy carbon disk. The solvent was THF containing 0.15 M tetrabutylammonium hexafluorophosphate (TBAPF6) as supporting electrolyte. All potential values in this work are referred to the Fc+/Fc (Fc = ferrocene) system, as Fc or Fc* (Fc* = decamethylferrocene) was added as an internal reference after each short series of measurements. E1/2 = (Epa + Epc)/2 of the Fc+/Fc was also measured as +0.47 V vs Fc*+/Fc* in the THF solution. Synthesis and Characterization Data of Polyfunctionalized Substrates for Intramolecular Coupling 1, 3−6, 8, 9, 11, 12, 14, 16, and 18. Synthesis of (E)-Trimethyl 5-(2-Iodophenyl)pent-1-ene1,4,4-tricarboxylate (1). (E)-Methyl 4-bromobut-2-enoate (0.98 mL, 8.33 mmol) was added over a solution of dimethyl malonate (0.87 mL, 7.57 mmol) and K2CO3 (1255 mg, 9.08 mmol) in MeCN (15 mL). The mixture was stirred at 60 °C during 16 h. Then K2CO3 was filtrated, and the solvent was removed. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give (E)-trimethyl but-3-ene-1,1,4-tricarboxylate (690 mg, 40%) as a yellowish oil. Its spectroscopic data were identical to the reported compound.78 2-Iodobenzyl bromide (1.07 g, 3.59 mmol) was added to a mixture of (E)-trimethyl but-3-ene-1,1,4-tricarboxylate (690 mg, 2.99 mmol) and NaH (60%) (144 mg, 3.59 mmol) in DMF (15 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The mixture was diluted with EtOAc, washed with HCl (10%), and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give 1 (1048 mg, 79%) as a yellowish oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 1H), 7.28−7.22 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.95−6.85 (m, 2H), 5.83 (d, J = 15.6 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 2H), 3.54 (s, 1H), 2.79 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 170.6 (C), 166.3 (C), 143.4 (CH), 140.1 (CH), 139.2 (C), 130.2 (CH), 129.0 (CH), 128.4 (CH), 124.3 (CH), 102.9 (C), 59.1 (C), 52.8 (CH3), 51.6 (CH3), 43.1 (CH2), 36.4 (CH2). HRMS (magnet-EI, 70 eV): m/z calcd for C17H19O6I [M]+ 446.0226, found 446.0233. Synthesis of (E)-Trimethyl 5-(2-Bromophenyl)pent-1-ene-1,4,4tricarboxylate (3). 1-Bromo-2-(bromomethyl)benzene79 (391 mg, 1.56 mmol) was added to a mixture of (E)-methyl 5-methylhex-2enoate (240 mg, 1.04 mmol) and NaH (60%) (63 mg, 1.58 mmol) in DMF (15 mL). The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with brine and HCl (10%), and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give 3 (313 mg, 75%) as a yellowish liquid. 1H NMR (300 MHz, CDCl3): δ 7.54 (d, J = 7.8 Hz, 1H), 7.25−7.14 (m, 2H), 7.13−7.04 (m, 1H), 6.99−6.84 (m, 1H), 5.84 (d, J = 15.6 Hz, 1H), 3.72 (s, 9H), 3.53 (s, 2H), 2.77 (d, J = 8.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 170.6 (C), 166.4 (C), 143.4 (CH), 135.6 (C), 133.3 (CH), 131.5 (CH), 128.9 (CH), 127.5 (CH), 127.0 (C), 124.4 (CH), 58.9 (C), 52.8 (CH3), 51.6 (CH3), 38.3 (CH2), 36.1 (CH2). HRMS (magnet-EI, 70 eV): m/z calcd for C17H19O6Br [M]+ 398.0365, found 398.0364. Synthesis of (E)-Trimethyl 5-(2-Chlorophenyl)pent-1-ene-1,4,4tricarboxylate (4). 1-(Bromomethyl)-2-chlorobenzene (97%) (221 mg, 1.04 mmol) was added to a mixture of (E)-methyl 5-methylhex-2enoate (200 mg, 0.87 mmol) and NaH (60%) (42 mg, 1.04 mmol) in DMF (6 mL). The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with HCl (10%), and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 4 (272 mg, 88%) as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ 7.46− 7.38 (m, 1H), 7.29−7.21 (m, 3H), 7.07−6.93 (m, 1H), 5.93 (d, J = 15.6 Hz, 1H), 3.80 (s, 9H), 3.57 (s, 2H), 2.82 (d, J = 8.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 170.6 (C), 166.3 (C), 143.3 (CH), 135.3

Figure 3. TEM image of particles produced upon the addition of 5 mL of Ni(acac)2 in THF (4 mM) to 8 mL of Cp2TiCl (10 mM).

10 nm range were formed. A clear aggregation was observed, and particles of 80−150 nm are shown. Moreover, EDX analysis of the particles demonstrated that the solid particles obtained are mainly constituted of nickel and are probably the source of the required Ni(0) complexes.77 These experimental results suggest that an initial ligand exchange between Ni(II) and Ti(III) generates a new Ni(II) complex, which can be easily reduced. The Lewis acidity of Cp2TiCl is known, and we can assume that the ligand exchange can produce cationic Ni(II) complexes, which are now more easily reduced by Mn or by Cp2TiCl itself. At this stage, Cp2TiCl would present a dual role: (a) favoring the reduction of Ni(II) species back to a catalytically active Ni(0) form via its activation by a Lewis acidic interaction toward its more efficient reduction and (b) acting as an efficient Lewis acid stimulating the α,β-unsaturated carbonyl for the insertion reaction.

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CONCLUSIONS We have shown that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to acrylates, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds interand intramolecularly with good functional group compatibility, which is essential for the development of free protecting group methodologies. Remarkably, α,β-unsaturated esters and amides are suitable substrates, thus expanding the substrate scope of related Ni-mediated transformations. Moreover, some insights about the complex mechanism of this multimetallic protocol have been reported.

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General Methods. All reagents and solvents were purchased from commercial sources and used without further purification. Dry THF was freshly distilled over Na/benzophenone. Flash column chromatography was carried out using silica gel 60 (230−400 mesh, Scharlab) as the stationary phase. Analytical TLC was performed on aluminum sheets coated with silica gel with fluorescent indicator UV254 (Alugram SIL G/UV254, Mackerey-Nagel, Germany) and observed under UV light (254 nm) and/or staining with phosphomolybdic acid solution and subsequent heating. All products were characterized by their NMR and MS spectra. All 1H and 13C NMR spectra were recorded on 300, 400, or 500 MHz spectrometers at a constant temperature of 298 K. Chemical shifts are reported in ppm and referenced to residual solvent. 1535



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7.21−7.15 (m, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.84−6.70 (m, 1H), 5.74 (d, J = 15.5 Hz, 1H), 3.72 (s, 6H), 3.54 (s, 2H), 2.77 (d, J = 7.6 Hz, 2H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.7 (C), 165.3 (C), 141.7 (CH), 140.1 (CH), 139.3 (C), 130.2 (CH), 128.9 (CH), 128.3 (CH), 126.5 (CH), 102.9 (C), 80.4 (C), 59.0 (C), 52.7 (CH3), 43.0 (CH2), 36.2 (CH2), 28.2 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C20H25O6I [M]+ 488.0696, found 488.0676. Synthesis of (E)-1-tert-Butyl 4,4-Dimethyl 5-(2-Bromophenyl)pent-1-ene-1,4,4-tricarboxylate (8). 1-Bromo-2-(bromomethyl)benzene (654 mg, 2.62 mmol) was added to a mixture of dimethyl 2-allylmalonate (0.28 mL, 1.74 mmol) and NaH (60%) (105 mg, 2.63 mmol) in DMF (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with HCl (10%) and brine, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/ hexane, 15:85) to give dimethyl 2-allyl-2-(2-bromobenzyl)malonate (268 mg, 45%) as a yellowish oil. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 7.8 Hz, 1H), 7.32−7.19 (m, 2H), 7.15−7.06 (m, 1H), 5.97− 5.72 (m, 1H), 5.27−4.97 (m, 2H), 3.75 (s, 6H), 3.53 (s, 2H), 2.69 (d, J = 6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 171.1 (C), 136.2 (C), 134.0 (CH), 133.1 (CH), 131.5 (CH), 128.6 (CH), 127.3 (CH), 126.0 (C), 119.1 (CH2), 59.1 (C), 52.5 (CH3), 37.9 (CH2), 32.9 (CH2). tert-Butyl acrylate (0.30 mL, 2.04 mmol) was added to a deoxygenated solution of Grubb’s second-generation catalyst (5.7 mg, 0.007 mmol) and dimethyl 2-allyl-2-(2-bromobenzyl)malonate (230 mg, 0.68 mmol) in dry CH2Cl2 (7 mL), and the resulting mixture was refluxed for 48 h. The solvent was removed, and the residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give 8 (128 mg, 43%) as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 7.8 Hz, 1H), 7.32−7.19 (m, 2H), 7.17−7.05 (m, 1H), 6.89−6.72 (m, 1H), 5.78 (d, J = 15.6 Hz, 1H), 3.74 (s, 6H), 3.55 (s, 2H), 2.77 (d, J = 7.3 Hz, 2H), 1.49 (s, 9H).13C NMR (75 MHz, CDCl3): δ 170.7 (C), 165.3 (C), 141.6 (CH), 135.8 (C), 133.2 (CH), 131.5 (CH), 128.8 (CH), 127.4 (CH), 126.6 (CH), 126.1 (C), 80.4 (C), 58.9 (C), 52.7 (CH3), 38.2 (CH2), 36.0 (CH2), 28.2 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C20H25O6Br [M]+ 440.0834, found 440.0829. Synthesis of (E)-Methyl 4-(N-(2-Iodophenyl)-4methylphenylsulfonamido)but-2-enoate (9). N-(2-Iodophenyl)-4methylbenzenesulfonamide84 (1g, 2.69 mmol) was added to a solution of NaH (60%) (161 mg, 4.03 mmol) in THF under Ar atmosphere. The resulting solution was stirred at room temperature for 1 h. Then a sample of (E)-methyl 4-bromobut-2-enoate (0.47 mL, 4.03 mmol) was added to this solution at 0 °C. The resulting solution was stirred at room temperature for 20 h. Then the mixture was diluted with EtOAc, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give 9 (740 mg, 60%) as a vitreous solid. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.31− 7.23 (m, 3H), 7.02 (d, J = 8.3 Hz, 2H), 6.95−6.85 (m, 1H), 5.80 (d, J = 15.7 Hz, 1H), 4.36−4.21 (m, 2H), 3.67 (s, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.9 (C), 144.2 (C), 141.9 (CH), 141.1 (C), 140.6 (CH), 136.3 (C), 131.3 (CH), 130.3 (CH), 129.7 (CH), 129.1 (CH), 128.2 (CH), 124.3 (CH), 102.3 (C), 52.6 (CH2), 51.8 (CH3), 21.7 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C18H18O4NIS [M]+ 471.0001, found 471.0010. Synthesis of (E)-Methyl 4-(N-(2-Bromophenyl)-4methylphenylsulfonamido)but-2-enoate (11). NaH (60%) (169 mg, 4.22 mmol) was added to a solution of N-(2-bromophenyl)-4methylbenzenesulfonamide85 (685 mg, 2.11 mmol) in dry THF (10 mL) under Ar atmosphere. The resulting solution was stirred at room temperature for 15 min. Then a sample of (E)-methyl 4-bromobut-2enoate (0.37 mL, 3.16 mmol) was added to this solution at 0 °C. The resulting solution was stirred at room temperature for 20 h. Then the mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 11 (250 mg, 29%) as a vitreous solid (53% of starting material was also recovered). 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.4

(C), 133.8 (C), 131.7 (CH), 129.9 (CH), 128.7 (CH), 126.8 (CH), 124.5 (CH), 58.8 (C), 52.7 (CH3), 51.6 (CH3), 35.9 (CH2), 35.8 (CH2). HRMS (magnet-EI, 70 eV): m/z calcd for C17H19O6Cl [M]+ 354.0870, found 354.0863. Synthesis of (E)-Trimethyl 5-(2-(((Trifluoromethyl)sulfonyl)oxy)phenyl)pent-1-ene-1,4,4-tricarboxylate (5). Et3N (1.14 mL, 8.19 mmol) was added to salicylaldehyde (500 mg, 4.09 mmol) in CH2Cl2 (10 mL), and the solution was stirred at room temperature for 10 min. Then a sample of trifluoromethanesulfonic anhydride (0.7 mL, 5.96 mmol) was slowly added to this solution. The resulting solution was stirred at room temperature for 3 h. The mixture was diluted with CH2Cl2, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 2-formylphenyl trifluoromethanesulfonate (860 mg, 82%) as a yellowish oil. Its spectroscopic data were identical to those for the reported compound.80 NaBH4 (187 mg, 5.05 mmol) was added to a solution of 2formylphenyl trifluoromethanesulfonate (860 mg, 3.37 mmol) in MeOH (20 mL). The resulting solution was monitored by TLC and stirred at room temperature until starting material disappeared (about 10 min). Then the mixture was diluted with EtOAc, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 2(hydroxymethyl)phenyl trifluoromethanesulfonate (710 mg, 83%) as a yellowish oil. Its spectroscopic data were identical to those for the reported compound.81 PBr3 (0.39 mL, 4.15 mmol) was added to a solution of 2(hydroxymethyl)phenyl trifluoromethanesulfonate (710 mg, 2.78 mmol) in Et2O (15 mL) at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched with cold water. Then the mixture was diluted with Et2O, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 5:95) to give 2(bromomethyl)phenyl trifluoromethanesulfonate (635 mg, 72%) as a yellowish oil. Its spectroscopic data were identical to those for the reported compound.82 2-(Bromomethyl)phenyl trifluoromethanesulfonate (500 mg, 1.56 mmol) was added to a mixture of (E)-methyl 5-methylhex-2-enoate (300 mg, 1.30 mmol) and NaH (60%) (63 mg, 1.58 mmol) in DMF (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 5 (295 mg, 48%) as a yellowish oil. 1H NMR (400 MHz, CDCl3): δ 7.37−7.21 (m, 4H), 6.87−6.77 (m, 1H), 5.83 (d, J = 15.2 Hz, 1H), 3.70 (s, 6H), 3.69 (s, 3H), 3.37 (s, 2H), 2.63 (d, J = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 170.3 (C), 166.2 (C), 148.7 (C), 142.4 (C), 132.7 (CH), 129.5 (CH), 128.6 (CH), 128.4 (CH), 125.0 (CH), 121.7 (CH), 118.6 (q, J = 320.4 Hz, CF3), 58.3 (C), 52.9 (CH3), 51.6 (CH3), 35.9 (CH2), 33.1 (CH2). HRMS (magnet-EI, 70 eV): m/z calcd for C18H19O9F3S [M]+ 468.0702, found 468.0703. Synthesis of (E)-1-tert-Butyl 4,4-Dimethyl 5-(2-iodophenyl)pent1-ene-1,4,4-tricarboxylate (6). 1-(Bromomethyl)-2-iodobenzene (517 mg, 1.74 mmol) was added to a mixture of dimethyl 2-allylmalonate (0.28 mL, 1.74 mmol) and NaH (60%) (84 mg, 2.09 mmol) in DMF (15 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with HCl (10%), and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give dimethyl 2-allyl-2-(2-iodobenzyl)malonate (300 mg, 45%) as a yellowish oil. Its spectroscopic data were identical to those for the reported compound.83 tert-Butyl acrylate (0.34 mL, 2.33 mmol) was added to a deoxygenated solution of Grubb’s second-generation catalyst (7 mg, 0.008 mmol) and compound dimethyl 2-allyl-2-(2-iodobenzyl)malonate (300 mg, 0.78 mmol) in dry CH2Cl2 (5 mL), and the resulting mixture was refluxed for 48 h. The solvent was removed, and the residue was submitted to flash chromatography (SiO2, EtOAc/ hexane, 15:85) to give 6 (201 mg, 53%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.7 Hz, 1H), 7.27−7.22 (m, 1H), 1536



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Synthesis of (E)-N-(2-Bromophenyl)-N-tosylbut-2-enamide (18). (E)-But-2-enoyl chloride (0.18 mL, 1.84 mmol) was slowly added to a mixture of Et3N (0.26 mL, 1.84 mmol) and N-(2-bromophenyl)-4methylbenzenesulfonamide (499 mg, 1.53 mmol) in CH2Cl2 (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with CH2Cl2, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give 18 (410 mg, 68%) as a white solid. Mp: 160−162 °C. 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.51−7.36 (m, 3H), 7.33 (d, J = 8.3 Hz, 2H), 7.03 (dq, J = 15.0, 6.9 Hz, 1H), 5.43 (d, J = 15.0 Hz, 1H), 2.44 (s, 3H), 1.71 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 164.5 (C), 147.0 (CH), 145.1 (C), 136.4 (C), 135.6 (C), 134.1 (CH), 132.6 (CH), 131.4 (CH), 129.9 (CH), 129.3 (CH), 128.8 (CH), 125.8 (C), 21.8 (CH3), 18.4 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H17O3NBrS [M + H]+ 394.0113, found 394.0111. Representative Procedure for Intramolecular Protocol. Rigorously deoxygenated dry THF (10 mL) was added to a deoxygenated mixture of Cp2TiCl2 (0.7 mmol), Mn (8.0 mmol), NiCl2 (0.2 mmol), and PPh3 (0.4 mmol) under Ar atmosphere, and the suspension was stirred at room temperature until it turned green (about 10 min). A solution of the previously synthesized polyfunctionalized substrate (Table 4, starting material, 1.0 mmol) in THF (2 mL) and Me3SiCl (4.0 mmol) were then added. The reaction mixture was stirred at room temperature for 16 h and then diluted with AcOEt, washed with HCl (10%), and dried over anhydrous Na2SO4, and the solvent was removed. The residue was submitted to flash column chromatography (SiO2, EtO Ac/hexane mixture) to give the corresponding cyclic products (Table 4, product, yield). Characterization Data of Cyclic Compounds 2, 7, 10, 13, 15, and 17. Dimethyl 4-(2-Methoxy-2-oxoethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2). Colorless oil, 63−72% yield. NMR spectra were identical to the reported data.83 Dimethyl 4-(2-tert-Butoxy-2-oxoethyl)-3,4-dihydronaphthalene2,2(1H)-dicarboxylate (7). Colorless oil, 56−58% yield. NMR spectra were identical to the reported data.83 Methyl 2-(1-Tosylindolin-3-yl)acetate (10). Vitreous solid, 34− 73% yield. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.12−6.95 (m, 3H), 4.15−4.05 (m, 1H), 3.69 (s, 3H), 3.68−3.62 (m, 1H), 3.60−3.49 (m, 1H), 2.53 (dd, J = 16.5, 5.1 Hz, 1H), 2.37 (s, 3H), 2.23 (dd, J = 16.5, 9.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 172.0 (C), 144.3 (C), 141.8 (C), 133.9 (C), 133.8 (C), 129.8 (CH), 129.4 (CH), 128.7 (CH), 127.4 (CH), 124.5 (CH), 124.0 (CH), 55.8 (CH2), 52.0 (CH3), 39.4 (CH2), 36.5 (CH), 21.7 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C18H19O4NS [M]+ 345.1035, found 345.1035. Methyl 2-(2-Tosyl-1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (13). Colorless oil, 58% yield. Compound 13 was isolated as a 5:1 mixture with reduced compound methyl 4-(N-benzyl-4methylphenylsulfonamido)butanoate. See the corresponding 1H NMR spectra in the Supporting Information. Spectroscopic data for compound 13: 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.31−7.26 (m, 1H), 7.18−7.12 (m, 2H), 7.06−6.99 (m, 1H), 4.61 (d, J = 15.0 Hz, 1H), 3.88−3.82 (m, 1H), 3.82 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.44−3.37 (m, 1H), 2.91 (dd, J = 16.8, 9.6 Hz, 1H), 2.81 (dd, J = 12.0, 3.0 Hz, 1H), 2.59 (dd, J = 16.8, 4.3 Hz, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.8 (C), 143.9 (C), 136.2 (C), 133.2 (C), 131.6 (C), 129.9 (CH), 128.7 (CH), 127.9 (CH), 127.2 (CH), 127.1 (CH), 126.6 (CH), 51.9 (CH3), 47.8 (CH2), 47.5 (CH2), 39.6 (CH2), 35.1 (CH), 21.7 (CH3). MS (EI, 70 eV): m/z calcd for C19H21O4NS [M]+ 359.12, found 359.12. Dimethyl 4-(2-Oxopropyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (15). Yellowish oil, 51% yield. 1H NMR (500 MHz, CDCl3): δ 7.22−7.01 (m, 4H), 3.73 (s, 3H), 3.67 (s, 3H), 3.51−3.45 (m, 1H), 3.34 (d, J = 16.0 Hz, 1H), 3.20 (d, J = 16.0 Hz, 1H), 2.97 (dd, J = 17.2, 4.7 Hz, 1H), 2.68 (dd, J = 17.2, 8.3 Hz, 1H), 2.67−2.62 (m, 1H), 2.20 (s, 3H), 1.86 (dd, J = 13.6, 10.2 Hz, 1H). 13C NMR

Hz, 1H), 7.33 (d, J = 7.9 Hz, 3H), 7.29−7.20 (m, 2H), 7.01−6.87 (m, 1H), 5.91 (d, J = 15.7 Hz, 1H), 4.39 (d, J = 28.7 Hz, 2H), 3.74 (s, 3H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.0 (C), 144.0 (C), 142.2 (CH), 137.6 (C), 136.6 (C), 134.1 (CH), 132.6 (CH), 130.2 (CH), 129.7 (CH), 128.2 (CH), 127.9 (CH), 125.2 (C), 124.0 (CH), 51.9 (CH2), 51.7 (CH3), 21.6 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C18H18O4NBrS [M]+ 423.0140, found 423.0145. Synthesis of (E)-Methyl 4-(N-(2-Iodobenzyl)-4methylphenylsulfonamido)but-2-enoate (12). (E)-Methyl 4-bromobut-2-enoate (278 mg, 1.55 mmol) was added to a mixture of N-(2iodobenzyl)-4-methylbenzenesulfonamide86 (400 mg, 1.03 mmol) and NaH (60%) (62 mg, 1.54 mmol) in THF (12 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 15:85) to give 12 (165 mg, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 3H), 6.95 (t, J = 7.6 Hz, 1H), 6.61−6.51 (m, 1H), 5.71 (d, J = 15.7 Hz, 1H), 4.39 (s, 2H), 3.90 (d, J = 4.8 Hz, 2H), 3.65 (s, 3H), 2.44 (s, 3H).13C NMR (100 MHz, CDCl3): δ 165.9 (C), 144.0 (C), 142.0 (CH), 139.6 (CH), 137.8 (C), 136.5 (C), 130.0 (CH), 129.7 (CH), 129.6 (CH), 128.8 (CH), 127.3 (CH), 123.7 (CH), 98.8 (C), 56.3 (CH2), 51.7 (CH3), 48.8 (CH2), 21.6 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C19H20O4NIS [M]+ 485.0158, found 485.0155. Synthesis of (E)-Dimethyl 2-(2-Iodobenzyl)-2-(4-oxopent-2-en-1yl)malonate (14). Methyl vinyl ketone (0.70 mL, 8.49 mmol) was added to a deoxygenated solution of Grubb’s second-generation catalyst (25 mg, 0.029 mmol) and dimethyl 2-allylmalonate (0.47 mL, 2.90 mmol) in dry CH2Cl2 (8 mL), and the resulting mixture was refluxed for 48 h. The solvent was removed, and the residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 2:8) to give (E)-dimethyl 2-(4-oxopent-2-en-1-yl)malonate (275 mg, 45%) as a yellowish oil. Its spectroscopic data were identical to the reported compound.87 1-(Bromomethyl)-2-iodobenzene (578 mg, 1.95 mmol) was added to a mixture of (E)-dimethyl 2-(4-oxopent-2-en-1-yl)malonate (275 mg, 1.30 mmol) and NaH (60%) (52 mg, 1.30 mmol) in THF (15 mL). The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with EtOAc, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 3:7) to give 14 (44 mg, 44%) as a yellowish oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.9 Hz, 1H), 7.28−7.22 (m, 1H), 7.15 (d, J = 7.15 Hz, 1H), 6.91 (t, J = 7.9 Hz, 1H), 6.77−6.66 (m, 1H), 6.01 (d, J = 15.9 Hz, 1H), 3.74 (s, 6H), 3.57 (s, 2H), 2.79 (d, J = 8.6 Hz, 2H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 198.2 (C), 170.6 (C), 142.4 (CH), 140.1 (C), 139.0 (C), 134.1 (CH), 130.0 (CH), 129.0 (CH), 128.4 (CH), 103.1 (C), 59.1 (C), 52.8 (CH3), 43.1 (CH2), 36.5 (CH2), 26.8 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H19O5I [M]+ 430.0277, found 430.0275. Synthesis of (E)-N-(2-Iodophenyl)-N-tosylbut-2-enamide (16). (E)-But-2-enoyl chloride (0.24 mL, 2.52 mmol) was slowly added to a mixture of Et3N (0.35 mL, 2.52 mmol) and N-(2-iodophenyl)-4methylbenzenesulfonamide (785 mg, 2.10 mmol) in CH2Cl2 (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. Then the mixture was diluted with CH2Cl2, washed with aqueous NH4Cl, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 20:80) to give 16 (520 mg, 56%) as a vitreous solid. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.4 Hz, 2H), 7.99 (dd, J = 7.7, 1.4 Hz, 1H), 7.47 (dt, J = 7.7, 1.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.37 - 7.30 (m, 1H), 7.18 (dt, J = 7.7, 1.4 Hz, 1H), 7.03 (dq, J = 15.0, 7.0 Hz, 1H), 5.41 (d, J = 15.0 Hz, 1H), 2.44 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.4 (C), 147.1 (CH), 145.2 (C), 140.7 (CH), 139.2 (C), 136.4 (C), 131.6 (CH), 131.3 (CH), 130.1 (CH), 129.6 (CH), 129.3 (CH), 122.2 (CH), 102.5 (C), 21.8 (CH3), 18.4 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H17O3NIS [M + H]+ 441.9974, found 441.9976. 1537



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(125 MHz, CDCl3): δ 207.3 (C), 172.3 (C), 171.3 (C), 137.8 (C), 134.0 (C), 129.2 (CH), 126.8 (CH), 126.5 (CH), 126.4 (CH), 53.8 (C), 53.0 (CH3), 52.9 (CH3), 50.6 (CH2), 35.4 (CH2), 34.9 (CH2), 31.4 (CH), 30.6 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H20O5 [M]+ 304.1311, found 304.1317. Ethyl 1-Tosylindolin-2-one (17). Vitreous solid, 48−55% yield. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.3 Hz, 1H), 7.38−7.32 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.23−7.13 (m, 2H), 3.45 (t, J = 5.6 Hz, 1H), 2.41 (s, 3H), 2.06−1.83 (m, 2H), 0.65 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 176.2 (C), 145.7 (C), 140.8 (C), 139.9 (C), 135.5 (C), 129.8 (CH), 128.7 (CH), 128.0 (CH), 124.8 (CH), 124.2 (CH), 113.8 (CH), 46.9 (CH), 24.4 (CH2), 21.8 (CH3), 9.5 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H17O3NS [M]+ 315.0929, found 315.0930. Synthesis Procedures and Characterization Data of Aryl Halides for Intermolecular Coupling. The following compounds were purchased from commercial sources and used without further purification: iodobenzene, 1-bromo-4-iodobenzene, 1-chloro-4-iodobenzene, methyl 4-iodobenzoate, 4-iodophenol, 3-iodobenzyl alcohol, bromobenzene, and 4-bromophenol. The following known compounds were synthesized by described methods, and they showed NMR spectra identical to the reported data: 1-iodo-4-methoxybenzene,88 4-iodophenyl acetate,89 tert-butyl((3-iodobenzyl)oxy)dimethylsilane,90 N-(4-iodophenyl)acetamide,91 N-(2-iodophenyl)acetamide,92 1-bromo-4-methoxybenzene,92 4-bromophenyl 4-methylbenzenesulfonate,93 4-bromophenyl acetate,94 N(4-bromophenyl)acetamide,95 and (4-bromophenoxy)-tert-butyldimethylsilane.96 Synthesis of 4-Iodophenyl 4-Methylbenzenesulfonate. pToluenesulfonyl chloride (357 mg, 1.87 mmol) was added to a mixture of Et3N (0.40 mL, 2.81 mmol) and 4-iodophenol (206 mg, 0.94 mmol) in CH2Cl2 (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 5 h. Then the mixture was diluted with CH2Cl2, washed with water and brine, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 1:9) to give 4-iodophenyl 4-methylbenzenesulfonate (230 mg, 66%) as a white solid. Mp: 101−104 °C. 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 7.7 Hz, 2H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 149.6 (C), 145.7 (C), 138.8 (CH), 132.2 (C), 130.0 (CH), 128.6 (CH), 124.6 (CH), 91.8 (C), 21.8 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C13H11O3SI [M]+ 373.9474, found 373.9471. Synthesis of N-(3-Iodophenyl)acetamide. Acetic anhydride (0.91 mL, 9.59 mmol) was slowly added to a mixture of Et3N (1.34 mL, 9.59 mmol) and 3-iodoaniline (700 mg, 3.20 mmol) in CH2Cl2 (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 2 h. Then the mixture was diluted with CH2Cl2, washed with water and NaOH (10%), and dried over anhydrous Na2SO4. After removal of the solvent, N-(3-iodophenyl)acetamide was obtained as a yellowish oil without any further purification (375 mg, 45%).97 1H NMR (300 MHz, CDCl3): δ 8.72 (bs, 1H), 7.95 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 2.16 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.6 (C), 139.2 (C), 133.2 (CH), 130.4 (CH), 129.0 (CH), 119.5 (CH), 94.1 (C), 24.5 (CH3). HRMS (TOF MS ES+): m/z calcd for C8H9NOI [M + H]+ 261.9729, found 261.9733 Synthesis of (((7-Iodohept-6-en-1-yl)oxy)methyl)benzene. PCC (1.11 g, 5.16 mmol) was added to a solution of 6(benzyloxy)hexan-1-ol98 (537 mg, 2.58 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 2 h. Then the mixture was submitted to flash chromatography (SiO2, EtOAc/ hexane, 3:7) to give 6-(benzyloxy)hexanal (1.16 g, 33%) as a yellowish oil. Its spectroscopic data were identical to those for the reported compound.99 Dry THF (30 mL) was added to a deoxygenated mixture of NaH (60%) (100.8 mg, 2.52 mmol) and (iodomethyl)triphenylphosphonium iodide (1.34 g, 2.52 mmol), and the reaction mixture was stirred at room temperature for 10 min. Then a solution of compound 6-(benzyloxy)hexanal (260 mg, 1.26 mmol) in THF (2

mL) was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with cold water. Then the mixture was diluted with EtOAc, washed with water, and dried over anhydrous Na2SO4. The residue was submitted to flash chromatography (SiO2, EtOAc/hexane, 5:95) to give (((7-iodohept-6en-1-yl)oxy)methyl)benzene (50 mg, 12%) as a colorless oil. It was isolated as 4:1 mixture of Z:E isomers. 1H NMR (300 MHz, CDCl3): δ 7.40−7.24 (m, 5H), 6.57−6.45 (m, 1H, E-isomer), 6.23−6.11 (m, 2H, Z-isomer), 5.98 (d, J = 14.3 Hz, 1H, E-isomer), 4.51 (s, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.25−2.10 (m, 2H), 1.74−1.54 (m, 2H), 1.54− 1.33 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 141.3 (CH), 138.8 (C), 128.5 (CH), 127.7 (CH), 82.5 (CH), 73.0 (CH2), 70.4 (CH2), 34.8 (CH2), 29.7 (CH2), 27.9 (CH2), 25.9 (CH2). HRMS could not be obtained. General Procedure for Intermolecular Coupling of Aryl Iodide Derivatives. Rigorously deoxygenated dry THF (10 mL) was added to a previously deoxygenated mixture of Cp2TiCl2 (0.7 mmol), Mn (8.0 mmol), NiCl2 (0.2 mmol) ,and PPh3 (0.4 mmol) under Ar atmosphere, and the suspension was stirred at room temperature until it turned green (about 10 min). A solution of the corresponding aryl iodide (1.0 mmol) in THF (2 mL), methyl acrylate (10 mmol), and Me3SiCl (4.0 mmol) were then added. The reaction mixture was stirred at room temperature for 16 h and then diluted with EtOAc, washed with HCl (10%), and dried over anhydrous Na2SO4, and the solvent removed. The residue was submitted to flash column chromatography (SiO2, EtOAc/hexane mixtures) to give the corresponding final products. General Procedure for Intermolecular Coupling of Aryl Bromide Derivatives. Rigorously deoxygenated dry THF (10 mL) was added to a previously deoxygenated mixture of Cp2TiCl2 (0.7 mmol), Mn (8.0 mmol), NiCl2 (0.2 mmol), and PPh3 (0.4 mmol) under Ar atmosphere, and the suspension was stirred at room temperature until it turned green (about 10 min). A solution of the corresponding aryl bromide (1.0 mmol) in THF (2 mL), methyl acrylate (or tert-butyl acrylate) (10 mmol), and Me3SiCl (4.0 mmol) were then added. The reaction mixture was stirred at 50 °C for 16 h and then diluted with EtOAc, washed with HCl (10%), and dried over anhydrous Na2SO4, and the solvent was removed. The residue was submitted to flash column chromatography (SiO2, EtOAc/hexane mixtures) to give the corresponding final products. Characterization Data of Intermolecular Coupling Products 19−38. Methyl 3-Phenylpropanoate (19). Colorless oil; 61% yield. NMR spectra were identical to the reported data.100 3-Phenylpropanenitrile (20). Colorless oil; 21% yield. NMR spectra were identical to the reported data.100 4-Phenyltetrahydro-2H-pyran-2-one (21). Yellowish oil; 41% yield. NMR spectra were identical to the reported data.101 tert-Butyl 3-Phenylpropanoate (22). Colorless oil; 42% yield. NMR spectra were identical to the reported data.102 Methyl 3-(4-(Tosyloxy)phenyl)propanoate (23). Vitreous solid; 65% yield (from aryl iodide), 67% yield (from aryl bromide). Compound 23 was isolated as a 10:1 mixture with methyl 3-(4tosylphenyl)acrylate. See the corresponding 1H NMR in the Supporting Information. Spectroscopic data of 23. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.56 (s, 3H), 2.82 (t, J = 7.7 Hz, 2H), 2.50 (t, J = 7.7 Hz, 2H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.0 (C), 148.2 (C), 145.4 (C), 139.6 (C), 132.6 (C), 129.8 (CH), 129.5 (CH), 128.6 (CH), 122.4 (CH), 51.7 (CH3), 35.5 (CH2), 30.3 (CH2), 21.8 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C17H18O5S [M]+ 334.0875, found 334.0877. Methyl 3-(4-Methoxyphenyl)propanoate (24). Vitreous solid; 38% yield (from aryl iodide), 70% yield (from aryl bromide). NMR spectra were identical to the reported data.103 Methyl 3-(4-Bromophenyl)propanoate (25). Yellowish oil; 40% yield. NMR spectra were identical to the reported data.104 Methyl 3-(4-Acetoxyphenyl)propanoate (26). Yellowish oil; 46% yield (from aryl iodide), 37% yield (from aryl bromide). 1H NMR (300 MHz, CDCl3): δ 7.20 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 3.67 (s, 3H), 2.95 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H), 1538



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2.29 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.3 (C), 169.6 (C), 149.2 (C), 138.2 (C), 129.4 (CH), 121.6 (CH), 51.7 (CH3), 35.7 (CH2), 30.4 (CH2), 21.2 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C12H14O4 [M]+ 222.0892, found 222.0882. Methyl 3-(4-Chlorophenyl)propanoate (27). Yellowish oil; 56% yield. NMR spectra were identical to the reported data.105 Compound 27 was isolated as a 10:1 mixture with methyl 3-(4-chlorophenyl)acrylate. See the 1H NMR in the Supporting Information. Methyl 4-(3-Methoxy-3-oxopropyl)benzoate (28). Colorless oil; 63% yield. NMR spectra were identical to the reported data.106 Compound 28 was isolated as a 15:1 mixture with methyl 3-(4carboxymethylphenyl)acrylate. See the 1H NMR in the Supporting Information. Methyl 3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)propanoate (29). Yellowish oil; 69% yield. 1H NMR (300 MHz, CDCl3): δ 7.31−6.90 (m, 4H), 4.66 (s, 2H), 3.61 (s, 3H), 2.90 (t, J = 7.8 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 141.8 (C), 140.5 (C), 128.5 (CH), 126.9 (CH), 126.1 (CH), 124.2 (CH), 65.0 (CH2), 51.6 (CH3), 35.8 (CH2), 31.1 (CH2), 26.1 (CH3), 18.5 (C), −5.1 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C13H19O3Si [M−C4H9]+ 251.1103, found 251.1098. Methyl 3-(4-Hydroxyphenyl)propanoate (30). Colorless oil; 59% yield. NMR spectra were identical to the reported data.107 Methyl 3-(3-(Hydroxymethyl)phenyl)propanoate (31). Colorless oil; 50% yield. 1H NMR (300 MHz, CDCl3): δ 7.15 (m, 4H), 4.60 (s, 2H), 3.62 (s, 3H), 2.91 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H). 13 C NMR (75 MHz, CDCl3): δ 173.4 (C), 141.3 (C), 140.8 (C), 128.7 (CH), 127.5 (CH), 126.9 (CH), 125.0 (CH), 65.2 (CH2), 51.7 (CH3), 35.6 (CH2), 30.9 (CH2). HRMS (magnet-EI, 70 eV): m/z calcd for C11H14O3 [M]+ 194.0943, found 194.0943. Methyl 3-(4-Acetamidophenyl)propanoate (32). 71% yield (from aryl iodide), 48% yield (from aryl bromide). Yellowish solid. Mp: 131−133 °C. 1H NMR (300 MHz, CDCl3): δ 8.12 (bs, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 3.64 (s, 3H), 2.88 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.7 Hz, 2H), 2.10 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.5 (C), 168.9 (C), 136.4 (C), 136.3 (C), 128.7 (CH), 120.4 (CH), 51.7 (CH3), 35.8 (CH2), 30.4 (CH2), 24.4 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C12H15O3N [M]+ 221.1052, found 221.1050. Methyl 3-(3-Acetamidophenyl)propanoate (33). Vitreous solid; 63% yield. 1H NMR (300 MHz, CDCl3): δ 7.37 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 3.63 (s, 3H), 2.86 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.10 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ 173.4 (C), 169.1 (C), 141.3 (C), 138.4 (C), 129.0 (CH), 124.1 (CH), 119.9 (CH), 118.1 (CH), 51.7 (CH3), 35.5 (CH2), 30.9 (CH2), 24.4 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C12H15O3N [M]+ 221.1052, found 221.1048. Methyl 3-(2-Acetamidophenyl)propanoate (34). 22% yield. White solid. Mp: 134−137 °C. 1H NMR (500 MHz, CDCl3): δ 8.75 (bs, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 3.65 (s, 3H), 2.88 (t, J = 7.7 Hz, 2H), 2.71 (t, J = 7.7 Hz, 2H), 2.23 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 175.4 (C), 169.0 (C), 135.7 (C), 132.6 (C), 129.9 (CH), 127.3 (CH), 125.5 (CH), 124.9 (CH), 52.2 (CH3), 35.3 (CH2), 25.3 (CH2), 24.3 (CH3). HRMS (magnet-EI, 70 eV): m/z calcd for C12H15O3N [M]+ 221.1052, found 221.1053. tert-Butyl 3-(4-((tert-Butyldimethylsilyl)oxy)phenyl)propanoate (35). Yellowish oil; 69% yield. NMR spectra were identical to the reported data.108 tert-Butyl 3-(4-Hydroxyphenyl)propanoate (36). Yellowish oil; 47% yield. NMR spectra were identical to the reported data.109 tert-Butyl 4-Phenylpent-4-enoate (37). Yellowish oil; 35% yield. NMR spectra were identical to the reported data.110 (Z)-tert-Butyl 8-(Benzyloxy)oct-4-enoate (38). Yellowish oil; 58% yield. 1H NMR (300 MHz, CDCl3): δ 7.37−7.22 (m, 4H), 5.48−5.28 (m, 2H), 4.50 (s, 1H), 3.46 (t, J = 6.6 Hz, 1H), 2.38−2.19 (m, 2H), 2.12−1.97 (m, 2H), 1.71−1.57 (m, 2H), 1.53−1.22 (m, 15H). 13C NMR (75 MHz, CDCl3): δ 172.7 (C), 138.8 (C), 131.1 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 80.3 (C), 73.0 (CH2),

70.5 (CH2), 35.7 (CH2), 29.8 (CH2), 29.6 (CH2), 28.3 (CH3), 27.3 (CH2), 26.0 (CH2), 23.1 (CH2). Transmission Electron Microscopy study. Obtaining particles. Rigorously deoxygenated dry THF (10 mL) was added to a previously deoxygenated mixture of Cp2TiCl2 (24 mg, 0.1 mmol) and Mn (63 mg, 1.1 mmol) under Ar atmosphere, and the suspension was stirred at room temperature until it turned green (about 10 min). The mixture was allowed to stand unperturbed, and then 8 mL of green supernatant was separated into a deoxygenated Schlenk flask. After that, 5 mL of a deoxygenated THF solution of Ni(acac)2 (4 mM) was added. An instant color change to dark green was observed, and within the next 15 min a dark gray precipitate was produced. The mixture was let to stand unperturbed overnight, and a black precipitated was obtained. Sample Preparation for TEM Analysis. The black precipitate obtained was dispersed in MeOH. A drop of the suspension was transferred to a gold grid and MeOH removed by evaporation. The grid was checked for specimen quality under an optical microscope before analysis in the electron microscope. TEM Analysis. TEM images were obtained with a high-resolution transmission electron microscope and STEM instrument operated at 200 kV and equipped with a EDX model EDAX. Representative micrographs of the solid particles are shown in Figure 1. The electron micrographs were enlarged, and the diameter of the metal particles was measured. The particle size determination was done by randomly measuring the size of several particles on the TEM micrographs. Particles in the range of 80−150 nm were found to be mainly nickel on EDX analysis. The presence of Ti, Mn, and Cl was also observed. The particles were supported in a gold grid, and although a copper grid is often used in this instrument, small amounts of Cu and Au are also observed.

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ASSOCIATED CONTENT

S Supporting Information *

Synthesis overview and copies of UV−vis absorption, 1H NMR, 13 C NMR, and EDX spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was funded by the MICINN (Spain) (project CTQ-2011.22455). I.R.M. thanks the Ministerio de Economiá (Spain) for a predoctoral FPU fellowship. D.M.A. thanks the Junta de Andaluciá (Spain) for a postdoctoral contract. A.M. thanks the University of Granada for a postdoctoral contract. A.G.C. thanks the Ministerio de Ciencia e Innovación (Spain) for a postdoctoral “Juan de la Cierva” contract.

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REFERENCES

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